Treatment of Renal Hypertension or Carotid Sinus Syndrome with Adventitial Pharmaceutical Sympathetic Denervation or Neuromodulation

ABSTRACT

Sympathetic nerves run through the adventitia surrounding renal arteries and are critical in the modulation of systemic hypertension. Hyperactivity of these nerves can cause renal hypertension, a disease prevalent in 30-40% of the adult population. Hypertension can be treated with neuromodulating agents (such as angiotensin converting enzyme inhibitors, angiotensin II inhibitors, or aldosterone receptor blockers), but requires adherence to strict medication regimens and often does not reach target blood pressure threshold to reduce risk of major cardiovascular events. A minimally invasive solution is presented here to reduce the activity of the sympathetic nerves surrounding the renal artery by locally delivering neurotoxic or nerve-blocking agents into the adventitia. Extended elution of these agents may also be accomplished in order to tailor the therapy to the patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/895,668, filed May 16, 2013 which is a continuation of U.S.application Ser. No. 12/765,720, filed Apr. 22, 2010, now U.S. Pat. No.8,465,752, which claims the benefit of prior provisional applications61/171,702, filed on Apr. 22, 2009 and 61/186,704, filed on Jun. 12,2009. The full disclosures of each of these applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices, systems, andmethods to treat disease. More particularly, the present inventionrelates to methods to treat hypertension by delivering agents to reducehyperactive sympathetic nerve activity in the adventitia of arteriesand/or veins that lead to the kidneys.

Hypertension, or high blood pressure, affects an estimated 30-40% of theworld's adult population. Renal, or renovascular, hypertension can becaused by hypoperfusion of the kidneys due to a narrowing of the renalarteries. The kidneys respond by giving off hormones that signal thebody to retain salt and water, causing the blood pressure to rise. Therenal arteries may narrow due to arterial injury or atherosclerosis.Despite effective drug regimens to regulate therenin-angiotensin-aldosterone pathway or to remove excess fluid from thebody and reduce blood pressure, some 20-30% of patients withhypertension suffer from resistant forms of the disease.

Resistant hypertension is a common clinical problem, caused when apatient is unable to control high blood pressure by systemic medicationalone. Resistant hypertension is especially a problem in old and obesepeople. Both of these demographics are growing. While symptoms are notobvious in these patients, cardiovascular risk is greatly increased whenthey are unable to control their blood pressure.

Hypertension is also caused by hyperactive renal sympathetic nerves.Renal sympathetic efferent and afferent nerves run generallylongitudinally along the outside of arteries leading from the aorta tothe kidneys. These nerves are critically important in the initiation andmaintenance of systemic hypertension. It has been shown that by severingthese nerves, blood pressure can be reduced. Exemplary experiments haveshown that denervation of the renal sympathetic nerves in rats withhyperinsulinimia-induced hypertension would reduce the blood pressure tonormotensive levels as compared to controls [Huang W-C, et al.Hypertension 1998; 32:249-254].

Percutaneous or endoscopic interventional procedures are very common inthe United States and other countries around the world. Intravascularcatheter systems are used for procedures such as balloon angioplasty,stent placement, atherectomy, retrieval of blood clots, photodynamictherapy, and drug delivery. All of these procedures involve theplacement of long, slender tubes known as catheters into arteries,veins, or other lumens of the body in order to provide access to thedeep recesses of the body without the necessity of open surgery.

In cases where renal arterial occlusion is causing hypertension thatcannot be controlled with medication, another potential therapy includesballoon angioplasty of the renal artery. In rare cases, surgical bypassgrafting may be considered as a therapeutic alternative. While renalangioplasty can be effective in reducing blood pressure, angioplasty isplagued with resulting restenosis due to elastic recoil, dissection, andneointimal hyperplasia. Renal stents may improve the result, but alsolead to restenosis or renarrowing of the artery due to neointimalhyperplasia.

While renal denervation had been performed with surgical methods in thepast, more recently a catheter-based therapy to heat and destroy thenerves from within the renal artery using radio-frequency ablation hasbeen studied. A human trial of the RF-ablation catheter method has alsobeen performed, with reported reduction in blood pressure in patientsenrolled in the catheter treatment arm of the study [Krum H, et al.Lancet 2009; 373(9671):1228-1230].

While the use of catheter-based radiofrequency (RF) denervation appearsto have a therapeutic effect, it is unknown what long-term implicationswill arise from the permanent damage caused to the vessel wall andnerves by the RF procedure. Radiofrequency energy denervates the vesselby creating heat in the vessel wall. The RF probe contacts the innerlining of the artery and the RF energy is transmitted through thetissue.

Anti-hypertension therapies can be problematic in a number of respects.First, hypertension is, for the most part, an asymptomatic disease.Patients can lack compliance to medicinal regimens due to theirperceived lack of symptoms. Second, even for patients that are highlycompliant to drug therapy, their target blood pressure may not bereached, with little to no recourse but for intervention. Third, whenintervention is taken (usually in the form of renal angioplasty and/orstenting), the long-term effects can include restenosis, progression ofchronic kidney disease, and ultimately kidney failure, becauseangioplasty leads to activation of an injury cascade that causesfibrosis and remodeling of the target artery. Fourth, surgicaltechniques to bypass or denervate renal arteries are radical and canlead to a number of surgical complications. And fifth, it is unknownwhether RF denervation of the artery will lead to further exacerbationof stenotic plaques, whether it is compatible with arteries in whichstents have been placed, whether the energy transmission through thickplaques or fibrous intima will be enough to effect the underlying nervesprocedure will work if the RF probe is in contact with a thick plaque inthe majority of patients, or whether the effective deadening of not onlynerves, but the smooth muscle in the arterial wall also, may lead toreactive hypervascular formation of the vasa vasorum and necrotizingplaques that, if ruptured, would result in acute kidney ischemia orchronic kidney disease. Thus, systems and protocols which are designedto produce sympathetic denervation with RF energy or surgical dissectionare limited in their applicability across the breadth of hypertensivedisease, or they may create new vascular complications that were notinherent to the underlying disease.

Neurotoxic agents like botulinum toxin, β-bungarotoxin (and other snakevenom toxins), tetanus toxin, and α-latrotoxin, have been used orproposed for use in many surgical techniques to block nerves, reducemuscle activity or paralyze muscles. Neuromuscular blocking agents liketubocurarine, alcuronium, pipecuronium, rocuronium, pancuronium,vecuronium (and other curare-like drugs, derived originally fromparalytic darts and arrows of South American tribes) have also been usedto induce paralysis by competing for cholinergic receptors at the motorend-plate. The curare-like agents are short acting in comparison to thetoxins. For example, botulinum toxin (which can be one of 7 differentserologically distinct types, from type A to type G) have been used andis FDA approved to treat strabismus, blepharospasm, hemifacial spasm,improvement of moderate to severe frown lines (cosmetic), and for thetreatment of excessive underarm sweating. Each of these uses forbotulinum toxin has shown treatment effect ranging from several monthsto more than a year.

The lethal dose of botulinum toxin is approximately 1 ng/kg asdetermined by experiments in mice. Currently available forms ofbotulinum toxin, Myobloc™ and Botox® have specific activity of 70 to 130U/ng and approximately 20 U/ng, respectively. One unit (1 U) is theamount of toxin found to cause death in 50% of mice tested 72 hoursafter intraperitoneal administration. Myobloc is available in 2500,5000, or 10000 U vials and is prescribed for dosage totaling 2500 to5000 U for the treatment of cervical dystonia. Botox is available in 100U per vial and is prescribed in dosages of 200-300 U for cervicaldystonia, 50-75 U for axillary hyperhidrosis, or 12 U spread across 6injections for blepharospasm. Active botulinum toxin is made up of aheavy chain and light chain with a total mass of 150 kDa; therefore,each 1 ng of active material contains approximately 4 billion activetoxin molecules.

Current antihypertensive drugs typically modulate blood pressure byinterrupting the renin-angiotensin-aldosterone axis or by acting as adiuretic. An earlier generation of antihypertensive agents had modes ofaction to directly impair the renal nervous system. Agents likeguanethidine, guanacline, and bretylium tosylate would modulatehypertension by preventing release of norepinephrine (also known asnoradrenaline) from sympathetic nerve terminals. With guanethidine,sympathectomy is accomplished by interfering with excitatory vesicularrelease and by replacing norepenephrine in synaptic vesicles.Sympathetic nerve failure has been previously demonstrated in rats andhamsters, but not humans, possibly because guanethidine was typicallydelivered systemically and the high local concentrations required toinduce sympathetic denervation in humans would come at the risk ofextremely undesirable systemic side effects. The use of guanethidine tocreate functional denervation in rodents is considered permanent, withno evidence of reinnervation of tissues for as long as 63 weeks aftertreatment in rats. In high doses, guanethidine inhibits mitochondrialrespiration and leads to neuron death. Importantly for this invention,guanethidine can be used to create local denervation in a dose-dependentmanner and without far-field effects. This has been seen in anexperiment comparing guanethidine injection into one hindquarter of ahamster and compared to a control injection on the contralateral side,performed by Demas and Bartness, J Neurosci Methods 2001. This is anadvantage for the use of the agent to localize the effect to a specificrenal artery without diffusion beyond the renal sympathetic ganglion tothe spinal cord or other nervous systems. Also of interest to thisinvention is the published observation that guanethidine selectivelydestroys postganglionic noradrenergic neurons (thus reducingnorepinephrine) while sparing dopaminergic fibers and nonneuralcatecholamine-secreting cells. It is this high level of specificity forwhich guanethidine has been chosen as a useful therapy. Finally,guanethidine was approved by FDA for use as a systemic antihypertensiveagent due to its ability to block sympathetic function, but has not beenapproved for local administration to cause long-term or permanentdenervation.

Locally delivered guanethidine has produced localized sympathectomy inhamster hindquarters, as observed by Demas and Bartness, 2001. In aseries of 10 to 20 unilateral injections of 2 microliters eachcontaining 5 to 10 micrograms of guanethidine per microliter, into theinguinal adipose tissue of hamsters, compared to similar injections ofplacebo into the contralateral inguinal adipose tissue, functionalsympathectomy of one side versus the other was seen with at least 200micrograms of delivery, whether spread across 10 or 20 injections of 2microliters each. The result was determined in this case by measuringthe norepinephrine content of the tissue 2 weeks after delivery, withsubstantial reduction in the side that had received guanethidine versusthe control (placebo) side.

Guanethidine has the chemical name Guanidine,[2-(hexahydro-1(2H)-azocinyl)ethyl]-, and is often supplied in thesulfate form, guanethidine sulfate or guanethidine monosulfate (CAS645-43-2) with chemical name Guanidine,[2-(hexahydro-1(2H)-azocinyl)ethyl]-, sulfate (1:1). Guanethidine hasbeen marketed under the trade name Ismelin.

Other agents have been shown to create partial or complete sympathectomyas well. These include immunosympathectomy agent anti-nerve growthfactor (anti-NGF); auto-immune sympathectomy agents anti-dopaminebeta-hydroxylase (anti-DBH) and anti-acetylcholinesterase (anti-AChe);chemical sympathectomy agents 6-hydroxyldopamine (6-OHDA), bretyliumtosylate, guanacline, and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine(DSP4); and immunotoxin sympathectomy agents OX7-SAP, 192-SAP,anti-dopamine beta-hydroxylase saporin (DBH-SAP), and anti-dopaminebeta-hydroxylase immunotoxin (DHIT). A full description of these agentsis found in Picklo M J, J Autonom Nery Sys 1997; 62:111-125. Phenol andethanol have also been used to produce chemical sympathectomy and arealso useful in the methods of this invention. Other sympatholytic agentsinclude alpha-2-agonists such as clonidine, guanfacine, methyldopa,guanidine derivatives like betanidine, guanethidine, guanoxan,debrisoquine, guanoclor, guanazodine, guanoxabenz and the like;imadazoline receptor agonists such as moxonidine, relmenidine and thelike; ganglion-blocking or nicotinic antagonists such as mecamylamine,trimethaphan and the like; MAOI inhibitors such as pargyline and thelike; adrenergic uptake inhibitors such as rescinnamine, reserpine andthe like; tyrosine hydroxylase inhibitors such as metirosine and thelike; alpha-1 blockers such as prazosin, indoramin, trimazosin,doxazosin, urapidil and the like; non-selective alpha blockers such asphentolamine and the like; serotonin antagonists such as ketanserin andthe like; and endothelin antagonists such as bosentan, ambrisentan,sitaxentan, and the like.

Additionally, agents that sclerose nerves can be used to createneurolysis or sympatholysis. Sclerosing agents that lead to theperivascular lesioning of nerves include quinacrine, chloroquine, sodiumtetradecyl sulfate, ethanolamine oleate, sodium morrhuate, polidocanol,phenol, ethanol, or hypertonic solutions.

Renal sympathetic nerve activity leads to the production ofnorepinephrine. It has been well established that renal sympathectomy(also known as renal artery sympathectomy or renal denervation) reducesnorepinephrine buildup in the kidney. This has been measured by studiesthat involved surgical denervation of the renal artery, published byConnors in 2004 for pigs, Mizelle in 1987 for dogs, and Katholi in 1981for rats. In fact, it has been shown that surgical denervation of onerenal artery with sham surgery on the contralateral renal artery resultsin reductions of approximately 90% or more in kidney norepinephrinecontent on the denervated side compared to the control side. Thisevidence of denervation is therefore used as a surrogate to testdenervation methods in large animals like pigs, since these animals donot develop essential hypertension normally. Further evidence of thelink between denervation and norepinephrine buildup has been presentedin norepinephrine spillover from the kidney, measured in the renal veinoutflow blood [as reported by Krum et al, Lancet 2009]. Further linkagehas been made between the ability to reduce renal norepinephrine inlarge animal models (such as porcine models) indicating the ability toreduce blood pressure in hypertensive human patients.

Complete sympathectomy of the renal arteries remains problematic due tothe side effects inherent with reducing blood pressure below normallevels. Over the past 30 years, an ongoing debate has taken place aroundthe presence and impact of a “J-curve” when relating the reduction ofhypertension to therapeutic benefit [Cruickshank J, Current CardiologyReports 2003; 5:441-452]. This debate has highlighted an important pointin the treatment of hypertension: that while reduction in blood pressuremay reduce cardiovascular morbidity and mortality rates, too great areduction leads to a reversal in benefit. With surgical sympathectomy,the renal efferent and afferent nerves are completely removed, so thereis no ability to “titrate” the amount of sympathectomy for a givenpatient. An improved method is proposed here for a therapy that can betitrated to the needs of the individual patient with adventitialdelivery of neurodegenerative or sympatholytic agents capable ofcreating dose-dependent sympathectomy. Given appropriate dose titration,therapy can be tailored to reach the bottom of the J-curve withoutovershooting and leading to hypotensive effects.

For all of these reasons, it would be desirable to provide additionaland improved methods and kits for the adventitial/perivascular deliveryof neurotoxic, sympatholytic, sympathetic nerve blocking agents orneuromuscular blocking agents (together with other agents that canmodulate nerve function, neuromodulating agents) to accomplishbiological and reversible denervation while not creating injury to theblood vessel or aggravating the underlying vascular disease. Inparticular, it would be beneficial to provide methods which specificallytarget therapeutic concentrations of the neuromodulating agents into theadventitia and perivascular tissue, where the sympathetic efferent andafferent nerves are located. It would be further beneficial if themethods could efficiently deliver the drugs into the targeted tissue andlimit or avoid the loss of drugs into the luminal blood flow. It wouldbe further beneficial if the methods could enhance the localization ofneuromodulating agents in the adventitia and peri-adventitia, avoidingdiffusion of agents to surrounding organs or nerves. It would be stillfurther beneficial if the persistence of such therapeutic concentrationsof the neuromodulating agents in the tissue were also increased,particularly in targeted tissues around the sympathetic nerves,including the adventitial tissue surrounding the blood vessel wall.Additionally, it would be beneficial to increase the uniformity ofneuromodulating agent delivery over the desired treatment zone. Stillfurther, it would be desirable if the tissue region or treatment zoneinto which the neuromodulating agent is delivered could be predicted andtracked with the use of visual imaging and positive feedback to anoperating physician. At least some of these objectives will be met bythe inventions described hereinafter.

2. Description of the Background Art

The following references are pertinent to intravascular and intraluminaldrug delivery: 0. Varenne and P. Sinnaeve, “Gene Therapy for CoronaryRestenosis: A Promising Strategy for the New Millenium?” CurrentInterventional Cardiology Reports, 2000, 2: 309-315. B. J. de Smet, et.al., “Metalloproteinase Inhibition Reduces Constrictive ArterialRemodeling After Balloon Angioplasty: A Study in the AtheroscleroticYucatan Micropig.” Circulation, 2000, 101: 2962-2967. A. W. Chan et.al., “Update on Pharmacology for Restenosis,” Current InterventionalCardiology Reports, 2001, 3: 149-155. Braun-Dullaeus R C, Mann M J, DzauV J. Cell cycle progression: new therapeutic target for vascularproliferative disease. Circulation. 1998; 98(1):82-9. Gallo R, PadureanA, Jayaraman T, Marx S, Merce Roque M, Adelman S, Chesebro J, Fallon J,Fuster V, Marks A, Badimon J J Inhibition of intimal thickening afterballoon angioplasty in porcine coronary arteries by targeting regulatorsof the cell cycle. Circulation. 1999; 99:2164-2170 Herdeg C, Oberhoff M,Baumbach A, Blattner A, Axel D I, Schroder S, Heinle H, Karsch K R.Local paclitaxel delivery for the prevention of restenosis: biologicaleffects and efficacy in vivo. J Am Coll Cardiol 2000 June;35(7):1969-76. Ismail A, Khosravi H, Olson H. The role of infection inatherosclerosis and coronary artery disease: a new therapeutic target.Heart Dis. 1999; 1(4):233-40. Lowe H C, Oesterle S N, Khachigian L M.Coronary in-stent restenosis: Current status and future strategies. J AmColl Cardiol. 2002 Jan. 16; 39(2):183-93. Fuchs S, Komowski R, Leon M B,Epstein S E. Anti-angiogenesis: A new potential strategy to inhibitrestenosis. Intl J Cardiovasc Intervent. 2001; 4:3-6. Kol A, Bourcier T,Lichtman A H, and Libby P. Chlamydial and human heat shock protein 60sactivate human vascular endothelium, smooth muscle cells, andmacrophages. J Clin Invest. 103:571-577 (1999). Farsak B, Vildirir A,Akyon Y, Pinar A, Oc M, Boke E, Kes S, and Tokgozogclu L. Detection ofChlamydia pneumoniae and Helicobacter pylori DNA in humanatherosclerotic plaques by PCR. J Clin Microbiol 2000; 38(12):4408-11Grayston J T. Antibiotic Treatment of Chlamydia pneumoniae for secondaryprevention of cardiovascular events. Circulation. 1998; 97:1669-1670.Lundemose A G, Kay J E, Pearce J H. Chlamydia trachomatis Mip-likeprotein has peptidyl-prolyl cis/trans isomerase activity that isinhibited by FK506 and rapamycin and is implicated in initiation ofchlamydial infection. Mol Microbiol. 1993; 7(5):777-83. Muhlestein J B,Anderson J L, Hammond E H, Zhao L, Trehan S, Schwobe E P, Carlquist J F.Infection with Chlamydia pneumoniae accelerates the development ofatherosclerosis and treatment with azithromycin prevents it in a rabbitmodel. Circulation. 1998; 97:633-636. K. P. Seward, P. A. Stupar and A.P. Pisano, “Microfabricated Surgical Device,” U.S. application Ser. No.09/877,653, filed Jun. 8, 2001. K. P. Seward and A. P. Pisano, “A Methodof Interventional Surgery,” U.S. application Ser. No. 09/961,079, filedSep. 20, 2001. K. P. Seward and A. P. Pisano, “A MicrofabricatedSurgical Device for Interventional Procedures,” U.S. application Ser.No. 09/961,080, filed Sep. 20, 2001. K. P. Seward and A. P. Pisano, “AMethod of Interventional Surgery,” U.S. application Ser. No. 10/490,129,filed Mar. 11, 2003.

The following references are pertinent to renal denervation therapy toreduce hypertension: Calhoun D A, et al, “Resistant Hypertension:Diagnosis, Evaluation and Treatment: A scientific statement from theAmerican Heart Association Professional Education Committee of theCouncil for High Blood Pressure Research,” Hypertension 2008;51:1403-1419. Campese V M, Kogosov E, “Renal Afferent DenervationPrevents Hypertension in Rats with Chronic Renal Failure,” Hypertension1995; 25:878-882. Ciccone C D and Zambraski E J, “Effects of acute renaldenervation on kidney function in deoxycorticosteroneacetate-hypertensive swine,” Hypertension 1986; 8:925-931. Connors B A,et al, “Renal nerves mediate changes in contralateral renal blood flowafter extracorporeal shockwave lithotripsy,” Nephron Physiology 2003;95:67-75. DiBona G F, “Nervous Kidney: Interaction between renalsympathetic nerves and the renin-angiotensin system in the control ofrenal function,” Hypertension 2000; 36:1083-1088. DiBona G F, “TheSympathetic Nervous System and Hypertension: Recent Developments,”Hypertension 2004; 43; 147-150. DiBona G F and Esler M, “TranslationalMedicine: The Antihypertensive Effect of Renal Denervation,” AmericanJournal of Physiology—Regulatory, Integrative and ComparativePhysiology. 2010 February; 298(2):R245-53. Grisk O, “Sympatho-renalinteractions in the determination of arterial pressure: role inhypertension,” Experimental Physiology 2004; 90(2):183-187. Huang W-C,Fang T-C, Cheng J-T, “Renal denervation prevents and reverseshyperinsulinemia-induced hypertension in rats,” Hypertension 1998;32:249-254. Krum H, et al, “Catheter-based renal sympathetic denervationfor resistant hypertension: a multicentre safety and proof-of-principlecohort study,” Lancet 2009; 373(9671):1228-1230. Joles J A and Koomans HA, “Causes and Consequences of Increased Sympathetic Activity on RenalDisease,” Hypertension 2004; 43:699-706. Katholi R E, Winternitz S R,Oparil S, “Role of the renal nerves in the pathogenesis of one-kidneyrenal hypertension in the rat,” Hypertension 1981; 3:404-409. Mizelle HL, et al, “Role of renal nerves in compensatory adaptation to chronicreductions in sodium uptake,” Am. J. Physiol. 1987; 252(Renal FluidElectrolyte Physiol. 21):F291-F298.

The following references are pertinent to neurotoxic or neuroblockingagents: Excerpt from Simpson L L, “Botulinum Toxin: a Deadly PoisonSheds its Negative Image,” Annals of Internal Medicine 1996;125(7):616-617: “Botulinum toxin is being used to treat such disordersas strabismus, spasmodic torticollis, and loss of detrusor sphinctercontrol. These disorders are all characterized by excessive efferentactivity in cholinergic nerves. Botulinum toxin is injected near thesenerves to block release of acetylcholine.” Clemens M W, Higgins J P,Wilgis E F, “Prevention of anastomotic thrombosis by Botulinum Toxin Ain an animal model,” Plast Rectonstr Surg 2009; 123(1) 64-70. De PaivaA, et al, “Functional repair of motor endplates after botulinumneurotoxin type A poisoning: Biphasic switch of synaptic activitybetween nerve sprouts and their parent terminals,” Proc Natl Acad Sci1999; 96:3200-3205. Morris J L, Jobling P, Gibbins I L, “Botulinumneurotoxin A attenuates release of norepinephrine but not NPY fromvasoconstrictor neurons,” Am J Physiol Heart Circ Physiol 2002;283:H2627-H2635. Humeau Y, Dousseau F, Grant N.J., Poulain B, “Howbotulinum and tetanus neurotoxins block neurotransmitter release,”Biochimie 2000; 82(5):427-446. Vincenzi F F, “Effect of Botulinum Toxinon Autonomic Nerves in a Dually Innervated Tissue,” Nature 1967;213:394-395. Carroll I, Clark J D, Mackey S, “Sympathetic block withbotulinum toxin to treat complex regional pain syndrome,” Annals ofNeurology 2009; 65(3):348-351. Cheng C M, Chen J S, Patel R P,“Unlabeled Uses of Botulinum Toxins: A Review, Part 1,” Am J Health-SystPharm 2005; 63(2):145-152. Fassio A, Sala R, Bonanno G, Marchi M,Raiteri M, “Evidence for calcium-dependent vesicular transmitter releaseinsensitive to tetanus toxin and botulinum toxin type F,” Neuroscience1999; 90(3):893-902. Baltazar G, Tome A, Carvalho A P, Duarte E P,“Differential contribution of syntaxin 1 and SNAP-25 to secretion innoradrenergic and adrenergic chromaffin cells,” Eur J Cell Biol 2000;79(12):883-91. Smyth L M, Breen L T, Mutafova-Yambolieva V N,“Nicotinamide adenine dinucleotide is released from sympathetic nerveterminals via a botulinum neurotoxin A-mediated mechanism in caninemesenteric artery,” Am J Physiol Heart Circ Physiol 2006;290:H1818-H1825. Foran P, Lawrence G W, Shone C C, Foster K A, Dolly JO, “Botulinum neurotoxin Cl cleaves both syntaxin and SNAP-25 in intactand permeabilized chromaffin cells: correlation with its blockade ofcatecholamine release,” Biochemistry 1996; 35(8):2630-6. Demas G E andBartness T J, “Novel Method for localized, functional sympatheticnervous system denervation of peripheral tissue using guanethidine,”Journal of Neuroscience Methods 2001; 112:21-28. Villanueva I, et al.,“Epinephrine and dopamine colocalization with norepinephrine in variousperipheral tissues: guanethidine effects,” Life Sci. 2003;73(13)1645-53. Picklo M J, “Methods of sympathetic degeneration andalteration,” Journal of the Autonomic Nervous System 1997; 62:111-125.Nozdrachev A D, et al., “The changes in the nervous structures under thechemical sympathectomy with guanethidine,” Journal of the AutonomicNervous System 1998; 74(2-3):82-85.

The following references are pertinent to self-assembling peptidehydrogel matrix, useful to extend pharmacokinetics as described in thisinvention: Koutsopoulos S, Unsworth L D, Nagai Y, Zhang S, “Controlledrelease of functional proteins through designer self-assembling peptidenanofiber hydrogel scaffold,” Proc Natl Acad Sci 2009; 106(12):4623-8.Nagai Y, Unsworth L D, Koutsopoulos S, Zhang S, “Slow release ofmolecules in self-assembling peptide nanofiber scaffold,” J Control Rel.2006; 115:18-25. BD™ PuraMatrix™ Peptide Hydrogel (Catalog No. 354250)Guidelines for Use, BD Biosciences, SPC-354250-G Rev 4.0. Erickson I E,Huang A H, Chung C, Li R T, Burdick J A, Mauck R L, Tissue EngineeringPart A. online publication ahead of print.doi:10.1089/ten.tea.2008.0099. Henriksson H B, Svanvik T, Jonsson M,Hagman M, Horn M, Lindahl A, Brisby H, “Transplantation of humanmesenchymal stems cells into intervertebral discs in a xenogeneicporcine model,” Spine 2009 Jan. 15; 34(2):141-8. Wang S, Nagrath D, ChenP C, Berthiaume F, Yarmush M L, “Three-dimensional primary hepatocyteculture in synthetic self-assembling peptide hydrogel,” Tissue Eng PartA 2008 February; 14(2):227-36. Thonhoff J R, Lou D I, Jordan P M, ZhaoX, Wu P, “Compatibility of human fetal neural stem cells with hydrogelbiomaterials in vitro,” Brain Res 2008 Jan. 2; 1187:42-51. Spencer N J,Cotanche D A, Klapperich C M, “Peptide- and collagen-based hydrogelsubstrates for in vitro culture of chick cochleae,” Biomaterials 2008March; 29(8):1028-42. Yoshida D, Teramoto A, “The use of 3-D culture inpeptide hydrogel for analysis of discoidin domain receptor 1-collageninteraction,” Cell Adh Migr 2007 April; 1(2):92-8. Kim M S, Yeon J H,Park J K, “A microfluidic platform for 3-dimensional cell culture andcell-based assays,” Biomed Microdevices 2007 February; 9(1):25-34.Misawa H, Kobayashi N, Soto-Gutierrez A, Chen Y, Yoshida A,Rivas-Carrillo J D, Navarro-Alvarez N, Tanaka K, Miki A, Takei J, UedaT, Tanaka M, Endo H, Tanaka N, Ozaki T, “PuraMatrix facilitates boneregeneration in bone defects of calvaria in mice,” Cell Transplant 2006;15(10):903-10. Yamaoka H, Asato H, Ogasawara T, Nishizawa S, TakahashiT, Nakatsuka T, Koshima I, Nakamura K, Kawaguchi H, Chung U I, Takato T,Hoshi K, “Cartilage tissue engineering using human auricularchondrocytes embedded in different hydrogel materials,” J Biomed MaterRes A 2006 July; 78(1):1-11. Bokhari M A, Akay G, Zhang S, Birch M A,“The enhancement of osteoblast growth and differentiation in vitro on apeptide hydrogel-polyHIPE polymer hybrid material,” Biomaterials 2005September; 26(25):5198-208. Zhang S, Semino C, Ellis-Behnke R, Zhao X,Spirio L, “PuraMatrix: Self-assembling Peptide Nanofiber Scaffolds.Scaffolding in Tissue Engineering,” CRC Press, 2005. Davis M E, Motion JP, Narmoneva D A, Takahashi T, Hakuno D, Kamm R D, Zhang S, Lee R T,“Injectable self-assembling peptide nanofibers create intramyocardialmicroenvironments for endothelial cells,” Circulation 111: 442-450,2005.

The following references are pertinent to carotid sinus syndrome (CSS)and adventitial denervation as a treatment option: Healey J, Connolly SJ, Morillo C A, “The management of patients with carotid sinus syndrome:is pacing the answer,” Clin Auton Res 2004 October; 14 Suppl 1:80-6.Toorop R J, Scheltinga M R, Bender M H, Charbon J A, Huige M C,“Effective surgical treatment of the carotid sinus syndrome,” JCardiovasc Surg (Torino) 2008 Oct. 24. Toorop R J, Scheltinga M R, MollF L, “Adventitial Stripping for Carotid Sinus Syndrome,” Ann Vasc Surg2009 Jan. 7.

BRIEF SUMMARY OF THE INVENTION

Methods and kits according to the present invention are able to achieveenhanced concentrations of neuromodulating agents in targeted tissuessurrounding a blood vessel, particularly adventitial tissues, moreparticularly renal artery and vein adventitial tissues which surroundthe renal sympathetic nerves. The methods rely on vascular adventitialdelivery of the neuromodulating agent using a catheter having adeployable needle. The catheter is advanced intravascularly to a targetinjection site (which may or may not be within a renal artery) in ablood vessel. The needle is advanced through the blood vessel wall sothat an aperture on the needle is positioned in adventitial tissuetypically within a perivascular region (defined below) surrounding theinjection site, and the neuromodulatng agent is delivered into theperivascular region through the microneedle.

This delivery protocol has been found to have a number of advantages.First, direct injection into the perivascular region has been found toimmediately provide relatively high concentrations of theneuromodulating agent in the adventitial tissue immediately surroundingthe injected tissue. Second, following injection, it has been found thatthe injected neuromodulating agents will distribute circumferentially tosubstantially uniformly surround the blood vessel at the injection siteas well as longitudinally to reach positions which are 1 cm, 2 cm, 5 cm,or more away from the injection site, depending upon the liquidformulation in which the drug is carried. In addition, some injectedneuromodulating agents may be found to distribute transmurallythroughout the endothelial and intimal layers of the blood vessel, aswell as in the media, or muscular layer, of the blood vessel wall.Pathways for the distribution of the neuromodulating agent are presentlybelieved to exist through the fatty connective tissue forming theadventitia and perivascular space and may also exist in the vasa vasorumand other capillary channels through the connective tissues. Third, thedelivered and distributed neuromodulating agent(s) will persist forhours or days, again depending on their carrier, their lipophilicity,and their potential to bind to cell surface receptors and undergoendocytosis. Thus, a prolonged therapeutic effect based on theneuromodulating agent may be achieved in both the adventitia and theblood vessel wall. Fourth, after the distribution has occurred, theconcentration of the neuromodulating agent throughout its distributionregion will be highly uniform. While the concentration of theneuromodulating agent at the injection site will always remain thehighest, concentrations at other locations in the peripheral adventitiaaround the injection site will usually reach at least about 10% of theconcentration at the injection site, often being at least about 25%, andsometimes being at least about 50%. Similarly, concentrations in theadventitia at locations longitudinally separated from the injection siteby about 5 cm will usually reach at least 5% of the concentration at theinjection site, often being at least 10%, and sometimes being at least25%. Fifth, the distribution can be traced with the use ofradio-contrast agents by X-ray (or by hyperechoic or hypoechoic contrastagents by ultrasound or MRI contrast agents by magnetic resonance) inorder to determine the extent of diffusion, allowing one to limit theinjection based on reaching a desirable diffusion region, increase theinjection based on the desire to reach a greater diffusion region, orchange the injection site based on an inadequate diffusion range basedon the location of the needle tip, which may be embedded in a thickplaque or located intraluminally from a thick calcification. Finally,after distribution of a neuromodulating agent such as guanethidine, theagent accumulates selectively within sympathetic neurons via the amineuptake pump, and can accumulate within neurons in vivo to concentrationsof 0.5 to 1.0 millimolar (mM).

The adventitial tissue surrounding arteries and veins in the bodycontains sympathetic nerves that provide signal pathways for theregulation of hormones and proteins secreted by the cells and organs ofthe body. The efferent (conducting away from the central nervous system)and afferent (conducting toward the central nervous system) sympatheticnerves that line the renal artery are held within this adventitialconnective tissue. The sympathetic nervous system is responsible for up-and down-regulation of chemicals in the body that lead to homeostasis.In the case of hypertension, the sympathetic nerves that run from thespinal cord to the kidneys signal the body to produce norepinephrine atsuperphysiological levels, which leads to a cascade of signals causing arise in blood pressure. Denervation of the renal arteries (and to someextent the renal veins) removes this response and allows a return tonormal blood pressure.

The benefits of the present invention are achieved by deliveringneuromodulating agents, such as neurotoxic, sympatholytic, sympatheticblocking agents or neuromuscular blocking agents (together and withother agents that can modulate the transmission of nerve signals) intothe adventitia or perivascular region surrounding a renal artery orvein. The perivascular region is defined as the region beyond externalelastic lamina of an artery or beyond the tunica media of a vein.Usually, injection will be made directly into the region of theadventitia comprised primarily of adventitial fat cells but alsocomprised of fibroblasts, vasa vasorum, lymphatic channels, and nervecells, and it has been found that the neuromodulating agent dispersesthrough the adventitia circumferentially, longitudinally, andtransmurally from injection site. Such distribution can provide fordelivery of therapeutically effective concentrations of theneuromodulating drugs directly to the area where nerve cells can beaffected. This is difficult or impossible to accomplish with otherdelivery techniques (such as parenteral hypodermic needle injection).

The adventitia is a layer of fatty tissue surrounding the arteries ofthe human and other vertebrate cardiovascular systems. The externalelastic lamina (EEL) separates the fatty adventitial tissue frommuscular tissue that forms the media of the arterial wall. Needles ofthe present invention pass through the muscular tissue of the bloodvessel and the EEL in order to reach the adventitia and perivascularspace into which the drug is injected. The renal arteries or veins thatare subject of this invention usually have an internal (lumen) diameterof between 1 mm and 10 mm, more often between 3 and 6 mm, particularlyafter angioplasty has been used to compress any plaque that may havebeen impinging on the lumen. The thickness of the intima and media,which separate the lumen from the EEL, are usually in the range from 200μm to 3 mm, more often in the range from 500 μm to 1 mm. The adventitialtissue surrounding the EEL may be several millimeters thick, but thesympathetic nerves that run to the kidneys are usually within 3 mmoutside the EEL, more often within 1 mm outside the EEL.

The neuromodulating agents injected in accordance with the methodsdescribed in this invention will typically either be in fluid formthemselves, or will be suspended in aqueous or fluid carriers in orderto permit dispersion of the neuromodulating agents through theadventitia. Drugs may also be suspended in self-assembling hydrogelcarriers in order to contain the diffusion and extend the retention ofagents in the area of tissue local to the injection site.

The delivery of neuromodulating agents into the adventitia outside theEEL leads to the direct targeting and interruption of the sympatheticnerve signaling pathway. With particular relevance to botulinum toxin,after delivery to the adventitia, the toxin binds with high affinity toreceptors on nerve endings, and the toxin molecules penetrate the cellmembrane via receptor-mediated endocytosis. Once in the nerve cell, thetoxin crosses the endosome membrane by pH-dependent translocation. Thetoxin then reaches the cytosol, where it cleaves polypeptides that areessential for exocytosis. Without these polypeptides, incoming nervesignals cannot trigger the release of acetylcholine, thus blocking anyoutgoing (or transmission of) nerve signals. Botulinum toxin has beenshown to block nerve activity for more than one year in humans, thoughrecovery of the nerve signal is seen over time.

Botulinum toxins have been used primarily for their interaction with theparasympathetic nervous system, due to the toxins' ability to inhibitrelease of acetylcholine at the neuromuscular junction. One aspect ofthe present invention is to deliver a neuromodulating agent such asbotulinum toxin to the adventitia of renal arteries to affect bothparasympathetic and sympathetic nerves. While preganglionic sympatheticnerves are cholinergic, post-ganglionic sympathetic nerves areadrenergic, expressing noradrenaline rather than acetylcholine. It hasbeen shown in the literature that botulinum toxin reduces the expressionof noradrenaline in addition to acetylcholine, which justifies its useas a neuromodulating agent for both parasympathetic and sympatheticnervous systems as further described in this application.

There have been rare reports of cardiovascular complications with theuse of botulinum neurotoxins, including myocardial infarction orarrhythmia, some with fatal outcomes. While some of these patients hadcardiovascular disease risk factors and the complication may have beenunrelated to the botulinum toxin injection, the release of high levelsof toxin into the bloodstream or the digestive tract is worrisome due tothe possibility that a patient might contract botulism.

Botulinum toxins cleave SNARE (Soluble N-sensitive factor Attachmentprotein REceptor) proteins, including synaptosomal-associated protein of25-kilodaltons (SNAP-25), syntaxin, and synaptobrevin (also known asvesicle-associated membrane protein, or VAMP). Each of these proteinsare required for vesicles containing acetylcholine or noradrenaline tobe released from nerve cells. In this manner, botulinum toxins preventthe exocytosis of the vesicles containing catecholemines oracetylcholine. Other pathways required for the release of acetylcholineor noradrenaline can also be modified, such as the down-regulation orabolishment of any of the SNARE proteins (which, in addition to SNAP-25,syntaxin and synaptobrevin, include synaptotagmin and Rab3a). Whilethese effects of botulinum toxin have most often been used to stop therelease of acetylcholine at the neuromuscular junction to prevent musclemovement or twitch, the toxin can also be exploited to prevent signalsfrom transmitting through the nerves in the renal artery adventitia. Thedifferent boltulinum toxin serotypes (A through G) are able to cleavedifferent components of the SNARE complex of proteins.

While cleavage of the SNARE proteins can be accomplished with botulinumtoxin, other methods may be employed to reduce or quell the hyperactivesignaling in the nerves that run through the renal artery adventitia orthe nerves that form other neural systems in the body. The reduction ofneurotransmitters, putative neurotransmitters, or neuroactive peptidescan accomplish the same goal of reducing nervous signal transmissionalong the renal arteries. Neurotransmitters, putative neurotransmitters,and neuroactive peptides include compounds of the amino acidergic systemsuch as γ-aminobutyrate (GABA), aspartate, glutamate, glycine, ortaurine; compounds of the cholinergic system such as acetylcholine;compounds of the histaminergic system such as histamine; compounds ofthe monoaminergic system such as adrenaline, dopamine, noradrenaline,serotonin, or tryptamine; compounds of the peptidergic system such asangiotensin, members of the bombesin family, bradykinin, calcitonin generelated peptide (CGRP), carnosine, caerulein, members of thecholecystokinin family, corticotropin, corticotropin releasing hormone,members of the dynorphin family, eledoisin, members of the endorphinfamily, members of the encephalin family, members of the gastrin family,luteinizing hormone releasing hormone (LHRH), melatonin, motilin,neurokinins, members of the neuromedin family, neuropeptide K,neuropeptide Y, neurotensin, oxytocin, peptide histidine isoleucine(PHI), physalaemin, sleep inducing peptides, somatostatin, substance K,substance P, thyroid hormone releasing hormone (TRH), vasoactiveintestinal peptide (VIP), or vasopressin; compounds of the purinergicsystem such as adenosine, ADP, AMP, or ATP; or compounds in the form ofgaseous neurotransmitters such as carbon monoxide or nitric oxide.

Neural block may be accomplished with agents such as lidocaine orbupivacaine, and it has been reported that neural block may be extendedwith the co-injection of botulinum toxin and bupivacaine versus thetoxin alone or the bupivacaine alone. The combination of agents can leadto an enhanced result because agents like bupivacaine block the influxof sodium ions into nerves, which serves to decrease action potentialand nerve firing. This can also be accomplished with co-injection oftoxin with calcium-channel blockers.

Sympathectomy may be accomplished with immunosympathectomy agents suchas anti-nerve growth factor (anti-NGF); auto-immune sympathectomy agentssuch as anti-dopamine beta-hydroxylase (anti-DBH) andanti-acetylcholineesterase (anti-AChe); chemical sympathectomy agentssuch as 6-hydroxydpoamine (6-OHDA), phenol, ethanol, bretylium tosylate,guanethidine, guanacline, andN-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4); immunotoxinsympathectomy agents such as OX7-SAP, 192-SAP, anti-dopaminebeta-hydroxylase saporin (DBH-SAP), and anti-dopamine beta-hydroxylaseimmunotoxin (DHIT); or combinations thereof. Other sympatholytic agentsinclude alpha-2-agonists such as clonidine, guanfacine, methyldopa,guanidine derivatives like betanidine, guanethidine, guanoxan,debrisoquine, guanoclor, guanazodine, guanoxabenz, guancydine, guanadreland the like; imadazoline receptor agonists such as moxonidine,relmenidine and the like; ganglion-blocking or nicotinic antagonistssuch as mecamylamine, trimethaphan and the like; MAOI inhibitors such aspargyline and the like; adrenergic uptake inhibitors such asrescinnamine, reserpine and the like; tyrosine hydroxylase inhibitorssuch as metirosine and the like; alpha-1 blockers such as prazosin,indoramin, trimazosin, doxazosin, urapidil and the like; non-selectivealpha blockers such as phentolamine and the like; serotonin antagonistssuch as ketanserin and the like; endothelin antagonists such asbosentan, ambrisentan, sitaxentan, and the like; and sclerotherapeuticagents such as quinacrine, chloroquine, sodium tetradecyl sulfate,ethanolamine oleate, sodium morrhuate, polidocanol, phenol, ethanol, orhypertonic solutions.

In the case of guanethidine, systemic administration with chronic, highdoses can cause functional sympathectomy, but at the expense of terribleside effects. Guanethidine causes sympathectomy by preventing therelease of norepinephrine from sympathetic nerve terminals byinterfering with the excitatory release of vesicles carryingnorepinephrine, by replacing noradrenaline in the synaptic vesicles, byinhibiting oxidative phosphorylation in mitochondria with an effectivedose in 50% of cells (ED₅₀) of 0.5 to 0.9 mM, by inhibiting retrogradetransport of trophic factors such as nerve growth factor, and also byexerting cytotoxic effects by an immune-mediated mechanism.

In addition to chemical sympatholysis, additional methods ofsympathectomy can be achieved such as by heating the nerves to withinthe range from 42° C. to 50° C.

In a first aspect of the present invention, a method for distributing aneuromodulating agent or combination of agents into the adventitialtissue and nerves surrounding a living vertebrate host's renal artery,such as a human renal artery, comprises positioning a microneedlethrough the wall of a renal blood vessel and delivering an amount of theneuromodulating agent or combination of agents therethrough.

The microneedle is inserted, preferably in a substantially normaldirection, into the wall of a vessel (artery or vein) to eliminate asmuch trauma to the patient as possible. Until the microneedle is at thesite of an injection, it is positioned out of the way so that it doesnot scrape against arterial or venous walls with its tip. Specifically,the microneedle remains enclosed in the walls of an actuator or sheathattached to a catheter so that it will not injure the patient duringintervention or the physician during handling. When the injection siteis reached, movement of the actuator along the vessel terminated, andthe actuator is operated to cause the microneedle to be thrustoutwardly, substantially perpendicular to the central axis of a vessel,for instance, in which the catheter has been inserted.

The aperture of the microneedle will be positioned so that it liesbeyond the external elastic lamina (EEL) of the blood vessel wall andinto the perivascular region surrounding the wall. Usually, the aperturewill be positioned at a distance from the inner wall of the blood vesselwhich is equal to at least 10% of the mean luminal diameter of the bloodvessel at the injection site. Preferably, the distance will be in therange from 10% to 75% of the mean luminal diameter.

When the aperture of the microneedle is located in the tissue outside ofthe EEL surrounding the blood vessel, the neuromodulating agent orcombination of agents are delivered through the needle aperture, atwhich point the agent or combination distributes substantiallycompletely circumferentially through adventitial tissue surrounding theblood vessel at the site of the microneedle. Usually, the agent willfurther distribute longitudinally along the blood vessel over a distanceof at least 1 to 2 cm, and can extend to greater distances depending ondosage (volume) injected, within a time period no greater than 60minutes, often within 5 minutes or less. While the concentration of theneuromodulating agent in the adventitia will decrease in thelongitudinal direction somewhat; usually, the concentration measured ata distance of 2 cm from the injection site will usually be at least 5%of the concentration measured at the same time at the injection site,often being at least 10%, frequently being as much as 25%, and sometimesbeing as much as 50%. The concentration profile is greatly dependent onthe size of the molecule or particle delivered into the adventitial andperivascular tissue. The concentration profile can be further tailoredby the use of different carriers and excipients within the liquid or gelformulation in which the agent is carried.

In a second aspect of the present invention, the location of theaperture may be detected in advance of placing the full dose ofneuromodulating agent into the adventitia by the use of, for example,X-ray, ultrasonic, or magnetic resonance imaging of a radio-contrastagent. The contrast agent may be delivered at the same time as thetherapeutic agent, either in or out of solution with the therapeuticagent, or it may be delivered prior to the therapeutic agent to detectand confirm that the needle aperture is in the desirable tissue locationoutside the EEL. After determining the successful placement of theneedle aperture, continued injection can be made through the needleunder image guidance. Such methods for delivering agents provide thephysician a positive visual feedback as to the location of the injectionand diffusion range, and also to titrate the dose based on diffusionrange and physiological response. The amounts of the agents deliveredinto the perivascular region may vary considerably, but imaging agentsdelivered before the therapeutic agent will usually be in the range of10 to 200 μl, and often will be in the range of 50 to 100 μl.Therapeutic agent injection will then typically be in the range from 10μl to 10 ml, more usually being from 100 μl to 5 ml, and often beingfrom 500 μl to 3 ml.

In a third aspect of the present invention, methods for treatment ofhypertension comprise positioning a microneedle through the wall of arenal artery or vein and delivering an effective dose of botulinum toxinto the adventitia surrounding vessels leading from the aorta to thekidney or from the kidney to the vena cava. A therapeutic effective doseof botulinum toxin to reduce neurotransmission and thereby reduce bloodpressure can be monitored by the operating physician and titrated basedon patient characteristics. This dose may be in the range from 10 pg(corresponding to approximately 0.2 U of Botox® or 1 U of Myobloc™) to25 ng (corresponding to approximately 500 U of Botox® or 2500 U ofMyobloc™), more usually being from 50 pg (corresponding to approximately1 U of Botox® or 5 U of Myobloc™) to 10 ng (corresponding toapproximately 200 U of Botox® or 1000 U of Myobloc™), and even moreusually being from 100 pg (corresponding to approximately 2 U of Botox®or 10 U of Myobloc™) to 2.5 ng (corresponding to approximately 50 U ofBotox® or 250 U of Myobloc™).

In a fourth aspect of the present invention, methods for treatment ofhypertension comprise positioning a microneedle through the wall of arenal artery or vein and delivering an effective dose of guanethidine tothe adventitia surrounding such vessels leading from the aorta to thekidney or from the kidney to the vena cava. A therapeutic effective doseof guanethidine to create sympathectomy and reduce norepinephrinerelease, thereby reducing blood pressure can be monitored by theoperating physician and titrated based on patient characteristics. Thisdose may be in the range from 10 μg to 200 mg, usually 50 μg to 100 mg,more usually being from 100 μg to 50 mg, and even more usually beingfrom 500 μg to 30 mg, and sometimes being from 500 μg to 10 mg.

In a fifth aspect of the present invention, methods for extending theactivity of neuromodulating agents in target tissues comprises the useof agents that are endocytosed by nerve cells and then remain in thecells for long periods of time before becoming inactive.

In a sixth aspect of the present invention, methods for extending theactivity of neuromodulating agents in target tissues comprises thedelivery of such agents within a hydrogel that has a capacity for selfassembly, such as a self-assembling peptide hydrogel matrix. Whenco-administered with the hydrogel material, molecules of the activeagent are trapped in a nanofiber matrix as the hydrogel self-assemblesdue to contact with physiologic conditions. The hydrogel matrix may havefibers with diameter from 1 to 100 nm, for example, and pores withdiameter from 1 to 300 nm, for example. Molecules trapped within thematrix may slowly diffuse through the porous structure or remain trappedwithin pores. The matrix may be slowly resorbed by the surroundingtissue, as peptide matrices are commonly known to do, and become simpleamino acids. As the matrix is resorbed, trapped molecules of the activeagent are then released into the surrounding tissues, leading to anability to extend the pharmacokinetics of the neuromodulating agents.This is particularly useful with agents that do not remain active withincells for extended times. Desirable pharmacokinetic profiles are in therange of weeks to months or even years.

An exemplary hydrogel for use with the methods described in thisinvention is a self-assembling peptide hydrogel that comprisesalternating hydrophilic and hydrophobic amino acids which, in thepresence of physiological conditions, will spontaneously self-organizeinto an interwoven nanofiber matrix with fiber diameters of 10-20 nm. Inthe presence of proteins and small molecules, the nanofiber matrix trapsthe bioactive molecules within pores ranging from 5 to 200 nm. Thisself-assembling peptide, acetyl-(Arg-Ala-Asp-Ala)₄-CONH₂[Ac-(RADA)₄-CONH₂] (PuraMatrix™), has been reported as an efficientslow-delivery carrier of small molecules. The release of proteins fromthe nanofiber matrix has been shown to include at least two phases. Thefirst is a “burst” of released material, wherein it has been theorizedthat the protein material that is loosely trapped within large poresdiffuses out rapidly (over a period of several hours), then a slowerrelease of more tightly trapped material occurs over at least severaldays and is governed by Brownian motion of the proteins moving throughthe tight matrix. A third aspect to the release kinetics is thebreakdown of the peptide matrix at its boundary, thus a release oftrapped protein as the peptide is resorbed by surrounding tissue. One ofthe advantages of the peptide hydrogel as compared to “traditional”hydrogels is that the breakdown of the peptide structure results only inamino acid byproducts, which are easily metabolized by the body.PuraMatrix is available from BD Bioscience as BD™ PuraMatrix™ PeptideHydrogel for research use only in 1% concentration. It is used primarilyas a cell culture agent, but with application for in vivo use in thedelivery of cells and bioactive agents. PuraMatrix has been studied forits uses as a matrix for engineering cartilage using mesenchymal cellsand chondrocytes, as a carrier of mesenchymal cells for spinal discinjury, as a hepatocyte culture matrix, to support differentiation ofhuman fetal neural stem cells in vitro, and other cell culture andregenerative medical applications. Biocompatibility studies ofPuramatrix have shown that it integrates well with tissue, much likeother extracellular matrix structures, and can be resorbed over a periodof several weeks. It has also been shown that functional vascularstructures can be seen in the nanofiber microenvironments by 28 daysafter injection. With specific relevance to this invention, PuraMatrixhas also been shown to have no deleterious effect on the proteins thatit entraps or elutes over time.

In yet another aspect of the present invention, methods to treat otherdiseases resulting from hyperactivity of sympathetic and parasympatheticnerves comprise delivery of neuoromodulating agents for the chemical orneuromodulating denervation of arteries. While this therapy may mostoften be applied to renal arteries, other vascular beds can benefit fromthese methods. For example, denervation of the carotid artery can beused to treat patients with carotid sinus syndrome (CSS), a conditionthat leads to dizziness and syncope, but can be rectified by carotidadventitial denervation.

In yet another aspect of the present invention, a method for treatingvascular disease comprises the delivery of neuromodulating agents to theadventitia around blood vessels. The development of atherosclerosis,vulnerable plaques, and the growth of hyperplastic neointima have eachbeen shown to rely on parasympathetic and sympathetic nerve signalingpathways. When interrupted, these signal pathways no longer produce theagents that end up causing the vascular inflammation that results inmortality and morbidity from associated ischemic complications.

Exemplary neuromodulating agents for creating chemical orneuromodulating denervation of renal arteries or other blood vessels inthe body include neurotoxins such as botulinum toxin (serotypes Athrough G), resinoferatoxin, alpha-bungarotoxin, beta-bungarotoxin,tetrodotoxin, tetanus toxin, alpha-latrotoxin, tetraethylamonium, andthe like; neuromuscular blocking agents like tubocurarine, alcuronium,pipecuronium, rocuronium, pancuronium, vecuronium, and the like; calciumchannel blockers such as amlodipine, diltiazem, felodiipine, isradipine,nicardipine, nifedipine, nisoldipine, verapamil, and the like; sodiumchannel blockers such as moricizine, propafenone, encainide, flecainine,tocainide, mexilietine, phenytoin, lidocaine, disopyramine, quinidine,procainamide, and the like; beta-adrenergic inhibitors such asacebutolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol,labetalol, metoprolol, nadolol, nebivolol, propranolol, pindolol,sotalol, timolol, and the like; acetylcholine receptor inhibitors suchas atropine and the like, immunosympathectomy agents such as anti-nervegrowth factor (anti-NGF) and the like; auto-immune sympathectomy agentssuch as anti-dopamine beta-hydroxylase (anti-DBH),anti-acetylcholineesterase (anti-AChe) and the like; chemicalsympathectomy agents such as 6-hydroxydpoamine (6-OHDA), phenol,ethanol, bretylium tosylate, guanidinium compounds (e.g. guanethidine orguanacline), N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and thelike; immunotoxin sympathectomy agents such as OX7-SAP, 192-SAP,anti-dopamine beta-hydroxylase saporin (DBH-SAP), anti-dopaminebeta-hydroxylase immunotoxin (DHIT) and the like; or combinationsthereof.

One particular advantage of this invention is the ability to reverse thetherapy in the case that a patient responds poorly to renal denervation.For example, if toxins are used to reduce neurotransmission, anti-toxinscan be delivered (either systemically or locally) to reverse the effectand improve the patient's health. Other methods for renal sympatheticdenervation have relied on surgical cutting of nerves or radiofrequencyenergy transmission to nerves to cause damage beyond which the nervescannot transmit signals. Each of these previous methods is irreversible(though the RF energy transmission can lead to non-permanent effectsthat may wear off after months to years). If patients respond poorly toeither the surgical or RF denervation procedures, there is thereforelittle recourse.

Another particular advantage of this invention is that side effects arelimited by the very low doses that lead to therapeutic effect, often inthe range from 0.1 to 2.5 ng in the case of botulinum neurotoxin oroften less than 5 mg of guanethidine (whereas systemic doses of 5-50mg/kg/day do not produce reliable sympathectomy in humans), because themethods described in this invention allow precise targeting ofneuromodulators into the tissue in which the sympathetic nerves arelocated.

Another particular advantage of this invention is that theneuromodulating agents delivered into the adventitia according to themethods described above do not lead to death of smooth muscle cells,inflammation, or restenosis, all of which can result from radiofrequencyenergy transmission into arterial walls from an endoluminal aspect.Rather, the agents directly target the sympathetic and parasympatheticnerves that run through the adventitia, leaving the smooth muscle andendothelium of the vessel in a functional state, healthy and able torespond to physiological signals coming from the blood or lymphtraveling around and through the vessel.

Another particular advantage of this invention is that theneuromodulating agents can be tracked during their delivery by the useof contrast agents. This allows physicians to ensure that large enoughdoses are given to fully treat the adventitia, but small enough dosesare used such that the diffusion is limited to the area of anatomicalinterest This limits the potential for neuromodulating agents to reachthe central nervous system. The use of imaging agents in coordinationwith blood pressure monitoring allows physicians to actively monitor theeffect of the dose while controlling the treatment range so as not toinfluence surrounding tissues or nervous systems.

In still further aspects of the present invention, kits for deliveringneuromodulating agents to a patient suffering from hypertension comprisea catheter, instructions for use of the catheter, and instructions fordelivery of the agent. The catheter has a microneedle which can beadvanced from a blood vessel lumen through a wall of the blood vessel toposition an aperture of the microneedle at a perivascular spacesurrounding the blood vessel. The instructions for use set forth any ofthe exemplary treatment protocols described above. The kit may alsoinclude one or more stents and one or more angioplasty balloons that canbe used to open the renal arteries and improve blood flow to thekidneys.

In a further aspect of the present invention, kits for deliveringneuromodulating agents to the vascular adventitia of patients sufferingfrom disease comprise a catheter, a neuromodulating agent which may ormay not be in formulation with a carrier that can extend the elutionkinetics of the agent into adventitial and adjacent tissues,instructions for use of the catheter, and dosage guidelines for theagent. The catheter has a microneedle which can be advanced from a bloodvessel lumen through the wall of the blood vessel to position anaperture of the microneedle at a location outside the EEL of the bloodvessel in the perivascular tissue or adventitia. The agent will usuallybe able to distribute circumferentially and longitudinally in theperivascular space and adventitia surrounding the blood vessel over adistance of at least 1 cm within a time of no greater than 5 minutes,usually within 1 minute or less. The instructions for use set forth anyof the exemplary treatment protocols described above. The kit may alsoinclude one or more stents and one or more angioplasty balloons that canbe used to open the renal arteries and improve blood flow to thekidneys.

The present invention provides methods that are enhanced by cathetersthat place a needle aperture outside the EEL of a blood vessel bydeploying the needle from the inside of the vessel. These catheters maytake on various forms. In one exemplary embodiment, a balloon orinflatable actuator is inflated to unfurl a balloon from around amicroneedle that his inserted roughly perpendicularly through the vesselwall, as further described in commonly owned U.S. Pat. Nos. 6,547,803;7,547,294; and 7,666,163. Another such exemplary embodiment employs aballoon that inflates and translates a needle and extrudes the needletip along a path into the vessel wall. Such an exemplary embodiment hasbeen shown with commonly owned U.S. Pat. No. 7,141,041. In each of theseexemplary embodiments, multiple components may be combined into the sameballoon or pressure component, such that one part of the wall isnon-distensible and another part of the wall is compliant orelastomeric, such that a single inflation step, whether it involvesvolume or pressure, may be useful to activate both the non-distensibleand compliant structures simultaneously or in series. Such enhancedembodiments for delivery catheters are described in U.S. Pat. No.7,691,080. Exemplary methods which can be used for deliveringneuromodulating agents into the adventitia are described in copendingcommonly owned application Ser. No. 10/691,119. The full disclosure ofeach of these commonly owned patents and applications are incorporatedherein by reference.

It is recognized that the use of these devices and techniques to deliverto the adventitia around renal arteries is useful in the treatment ofhypertension, it is also evident that the use of these devices andtechniques can be applied to other arteries, such as the carotid artery,to accomplish similar goals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic, perspective view of an intraluminal injectioncatheter suitable for use in the methods and systems of the presentinvention.

FIG. 1B is a cross-sectional view along line 1B-1B of FIG. 1A.

FIG. 1C is a cross-sectional view along line 1C-1C of FIG. 1A.

FIG. 2A is a schematic, perspective view of the catheter of FIGS. 1A-1Cshown with the injection needle deployed.

FIG. 2B is a cross-sectional view along line 2B-2B of FIG. 2A.

FIG. 3 is a schematic, perspective view of the intraluminal catheter ofFIGS. 1A-1C injecting therapeutic agents into an adventitial spacesurrounding a body lumen in accordance with the methods of the presentinvention.

FIGS. 4A-4D are cross-sectional views of the inflation process of anintraluminal injection catheter useful in the methods of the presentinvention.

FIGS. 5A-5C are cross-sectional views of the inflated intraluminalinjection catheter useful in the methods of the present invention,illustrating the ability to treat multiple lumen diameters.

FIG. 6 is a perspective view of a needle injection catheter useful inthe methods and systems of the present invention.

FIG. 7 is a cross-sectional view of the catheter FIG. 6 shown with theinjection needle in a retracted configuration.

FIG. 8 is a cross-sectional view similar to FIG. 7, shown with theinjection needle laterally advanced into luminal tissue for the deliveryof therapeutic or diagnostic agents according to the present invention.

FIG. 9 is a schematic illustration of an artery together withsurrounding tissue illustrating the relationship between theperivascular tissue, the adventitia, and the blood vessel wallcomponents.

FIG. 10A is a schematic illustration of the kidney and arterialstructure that brings blood to the kidney.

FIG. 10B is a schematic illustration of FIG. 10A with sympathetic nervesshown leading from the aorta around the renal artery to the kidney.

FIG. 10C is a cross-sectional view along line 10C-10C of FIG. 10B.

FIGS. 11A-11C are cross-sectional views similar to FIGS. 4A and 4D,shown with the injection needle advanced into the adventitia forprogressive delivery of agents to sympathetic nerves according to thepresent invention.

FIG. 11D is a cross-sectional view along line 11D-11D of FIG. 11A.

FIG. 11E is a cross-sectional view along line 11E-11E of FIG. 11B.

FIG. 11F is a cross-sectional view along line 11F-11F of FIG. 11C.

FIG. 12 is an illustration showing how botulinum toxin interacts withnerve cells to prevent the exocytosis of acetylcholine.

FIG. 13 is a graphical presentation of experimental data describedherein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will preferably utilize microfabricated cathetersfor intravascular injection. The following description and FIGS. 1-8provide three representative embodiments of catheters havingmicroneedles suitable for the delivery of a neuromodulating agent into aperivascular space or adventitial tissue. A more complete description ofthe catheters and methods for their fabrication is provided in U.S. Pat.Nos. 7,141,041; 6,547,803; 7,547,294; 7,666,163 and 7,691,080, the fulldisclosures of which have been incorporated herein by reference.

The present invention describes methods and kits useful for the deliveryof neuromodulating agents into the adventitia around renal arteries inorder to reduce blood pressure in the treatment of hypertension. In eachkit, a delivery catheter may be combined with instructions for use and atherapeutically effective amount of a neuromodulating agent as definedabove.

As shown in FIGS. 1A-2B, a microfabricated intraluminal catheter 10includes an actuator 12 having an actuator body 12 a and centrallongitudinal axis 12 b. The actuator body more or less forms a U-shapedor C-shaped outline having an opening or slit 12 d extendingsubstantially along its length. A microneedle 14 is located within theactuator body, as discussed in more detail below, when the actuator isin its unactuated condition (furled state) (FIG. 1B). The microneedle ismoved outside the actuator body when the actuator is operated to be inits actuated condition (unfurled state) (FIG. 2B).

The actuator may be capped at its proximal end 12 e and distal end 12 fby a lead end 16 and a tip end 18, respectively, of a therapeuticcatheter 20. The catheter tip end serves as a means of locating theactuator inside a body lumen by use of a radio opaque coatings ormarkers. The catheter tip also forms a seal at the distal end 12 f ofthe actuator. The lead end of the catheter provides the necessaryinterconnects (fluidic, mechanical, electrical or optical) at theproximal end 12 e of the actuator.

Retaining rings 22 a and 22 b are located at the distal and proximalends, respectively, of the actuator. The catheter tip is joined to theretaining ring 22 a, while the catheter lead is joined to retaining ring22 b. The retaining rings are made of a thin, on the order of 10 to 100microns (μm), substantially flexible but relatively non-distensiblematerial, such as Parylene (types C, D or N), or a metal, for example,aluminum, stainless steel, gold, titanium or tungsten. The retainingrings form a flexible but relatively non-distensible substantially“U”-shaped or “C”-shaped structure at each end of the actuator. Thecatheter may be joined to the retaining rings by, for example, abutt-weld, an ultra sonic weld, integral polymer encapsulation or anadhesive such as an epoxy or cyanoacrylate.

The actuator body further comprises a central, expandable section 24located between retaining rings 22 a and 22 b. The expandable section 24includes an interior open area 26 for rapid expansion when an activatingfluid is supplied to that area. The central section 24 is made of athin, semi-flexible but relatively non-distensible or flexible butrelatively non-distensible, expandable material, such as a polymer, forinstance, Parylene (types C, D or N), silicone, polyurethane orpolyimide. The central section 24, upon actuation, is expandablesomewhat like a balloon-device.

The central section is capable of withstanding pressures of up to about200 psi upon application of the activating fluid to the open area 26.The material from which the central section is made of is flexible butrelatively non-distensible or semi-flexible but relativelynon-distensible in that the central section returns substantially to itsoriginal configuration and orientation (the unactuated condition) whenthe activating fluid is removed from the open area 26. Thus, in thissense, the central section is very much unlike a balloon which has noinherently stable structure.

The open area 26 of the actuator is connected to a delivery conduit,tube or fluid pathway 28 that extends from the catheter's lead end tothe actuator's proximal end. The activating fluid is supplied to theopen area via the delivery tube. The delivery tube may be constructed ofTeflon© or other inert plastics. The activating fluid may be a salinesolution or a radio-opaque dye.

The microneedle 14 may be located approximately in the middle of thecentral section 24. However, as discussed below, this is not necessary,especially when multiple microneedles are used. The microneedle isaffixed to an exterior surface 24 a of the central section. Themicroneedle is affixed to the surface 24 a by an adhesive, such ascyanoacrylate. Alternatively, the microneedle maybe joined to thesurface 24 a by a metallic or polymer mesh-like structure 30 (See FIG.2A), which is itself affixed to the surface 24 a by an adhesive. Themesh-like structure may be-made of, for instance, steel or nylon.

The microneedle includes a sharp tip 14 a and a shaft 14 b. Themicroneedle tip can provide an insertion edge or point. The shaft 14 bcan be hollow and the tip can have an outlet port 14 c, permitting theinjection of a neuromodulating or drug into a patient. The microneedle,however, does not need to be hollow, as it may be configured like aneural probe to accomplish other tasks. As shown, the microneedleextends approximately perpendicularly from surface 24 a. Thus, asdescribed, the microneedle will move substantially perpendicularly to anaxis of a lumen into which has been inserted, to allow direct punctureor breach of body lumen walls.

The microneedle further includes a neuromodulating or drug supplyconduit, tube or fluid pathway 14 d which places the microneedle influid communication with the appropriate fluid interconnect at thecatheter lead end. This supply tube may be formed integrally with theshaft 14 b, or it may be formed as a separate piece that is later joinedto the shaft by, for example, an adhesive such as an epoxy. Themicroneedle 14 may be bonded to the supply tube with, for example, anadhesive such as cyanoacrylate.

The needle 14 may be a 30-gauge, or smaller, steel needle.Alternatively, the microneedle may be microfabricated from polymers,other metals, metal alloys or semiconductor materials. The needle, forexample, may be made of Parylene, silicon or glass. Microneedles andmethods of fabrication are described in U.S. application Ser. No.09/877,653, filed Jun. 8, 2001, entitled “Microfabricated SurgicalDevice”, the entire disclosure of which is incorporated herein byreference.

The catheter 20, in use, is inserted through an opening in the body(e.g. for bronchial or sinus treatment) or through a percutaneouspuncture site (e.g. for artery or venous treatment) and moved within apatient's body passageways 32, until a specific, targeted region 34 isreached (see FIG. 3). The targeted region 34 may be the site of tissuedamage or more usually will be adjacent the sites typically being within100 mm or less to allow migration of the therapeutic or diagnosticagent. As is well known in catheter-based interventional procedures, thecatheter 20 may follow a guide wire 36 that has previously been insertedinto the patient. Optionally, the catheter 20 may also follow the pathof a previously-inserted guide catheter (not shown) that encompasses theguide wire.

During maneuvering of the catheter 20, well-known methods of X-rayfluoroscopy or magnetic resonance imaging (MRI) can be used to image thecatheter and assist in positioning the actuator 12 and the microneedle14 at the target region. As the catheter is guided inside the patient'sbody, the microneedle remains furled or held inside the actuator body sothat no trauma is caused to the body lumen walls.

After being positioned at the target region 34, movement of the catheteris terminated and the activating fluid is supplied to the open area 26of the actuator, causing the expandable section 24 to rapidly unfurl,moving the microneedle 14 in a substantially perpendicular direction,relative to the longitudinal central axis 12 b of the actuator body 12a, to puncture a body lumen wall 32 a. It may take only betweenapproximately 100 milliseconds and five seconds for the microneedle tomove from its furled state to its unfurled state.

The microneedle aperture, may be designed to enter body lumen tissue 32b as well as the adventitia, media, or intima surrounding body lumens.Additionally, since the actuator is “parked” or stopped prior toactuation, more precise placement and control over penetration of thebody lumen wall are obtained.

After actuation of the microneedle and delivery of the agents to thetarget region via the microneedle, the activating fluid is exhaustedfrom the open area 26 of the actuator, causing the expandable section 24to return to its original, furled state. This also causes themicroneedle to be withdrawn from the body lumen wall. The microneedle,being withdrawn, is once again sheathed by the actuator.

Various microfabricated devices can be integrated into the needle,actuator and catheter for metering flows, capturing samples ofbiological tissue, and measuring pH. The device 10, for instance, couldinclude electrical sensors for measuring the flow through themicroneedle as well as the pH of the neuromodulating being deployed. Thedevice 10 could also include an intravascular ultrasonic sensor (IVUS)for locating vessel walls, and fiber optics, as is well known in theart, for viewing the target region. For such complete systems, highintegrity electrical, mechanical and fluid connections are provided totransfer power, energy, and neuromodulatings or biological agents withreliability.

By way of example, the microneedle may have an overall length of betweenabout 200 and 3,000 microns (μm). The interior cross-sectional dimensionof the shaft 14 b and supply tube 14 d may be on the order of 20 to 250um, while the tube's and shaft's exterior cross-sectional dimension maybe between about 100 and 500 μm. The overall length of the actuator bodymay be between about 5 and 50 millimeters (mm), while the exterior andinterior cross-sectional dimensions of the actuator body can be betweenabout 0.4 and 4 mm, and 0.5 and 5 mm, respectively. The gap or slitthrough which the central section of the actuator unfurls may have alength of about 4-40 mm, and a cross-sectional dimension of about 50 μmto 4 mm. The diameter of the delivery tube for the activating fluid maybe between 100 and 500 μm. The catheter size may be between 1.5 and 15French (Fr).

Referring to FIGS. 4A-4D, an elastomeric component is integrated intothe wall of the intraluminal catheter of FIG. 1-3. In FIG. 4A-D, theprogressive pressurization of such a structure is displayed in order ofincreasing pressure. In FIG. 4A, the balloon is placed within a bodylumen L. The lumen wall W divides the lumen from periluminal tissue T,or adventitia A*, depending on the anatomy of the particular lumen. Thepressure is neutral, and the non-distensible structure forms a U-shapedinvoluted balloon 12 similar to that in FIG. 1 in which a needle 14 issheathed. While a needle is displayed in this diagram, other workingelements including cutting blades, laser or fiber optic tips,radiofrequency transmitters, or other structures could be substitutedfor the needle. For all such structures, however, the elastomeric patch400 will usually be disposed on the opposite side of the involutedballoon 12 from the needle 14.

Actuation of the balloon 12 occurs with positive pressurization. In FIG.4B, pressure (+ΔP₁) is added, which begins to deform the flexible butrelatively non-distensible structure, causing the balloon involution tobegin its reversal toward the lower energy state of a round pressurevessel. At higher pressure+ΔP₂ in FIG. 4C, the flexible but relativelynon-distensible balloon material has reached its rounded shape and theelastomeric patch has begun to stretch. Finally, in FIG. 4D at stillhigher pressure+ΔP₃, the elastomeric patch has stretched out toaccommodate the full lumen diameter, providing an opposing force to theneedle tip and sliding the needle through the lumen wall and into theadventitia A. Typical dimensions for the body lumens contemplated inthis figure are between 0.1 mm and 50 mm, more often between 0.5 mm and20 mm, and most often between 1 mm and 10 mm. The thickness of thetissue between the lumen and adventitia is typically between 0.001 mmand 5 mm, more often between 0.01 mm and 2 mm and most often between0.05 mm and 1 mm. The pressure+ΔP useful to cause actuation of theballoon is typically in the range from 0.1 atmospheres to 20atmospheres, more typically in the range from 0.5 to 20 atmospheres, andoften in the range from 1 to 10 atmospheres.

As illustrated in FIGS. 5A-5C, the dual modulus structure shown in FIGS.4A-4D provides for low-pressure (i.e., below pressures that may damagebody tissues) actuation of an intraluminal medical device to placeworking elements such as needles in contact with or through lumen walls.By inflation of a constant pressure, and the elastomeric material willconform to the lumen diameter to provide full apposition. Dual modulusballoon 12 is inflated to a pressure +ΔP₃ in three different lumendiameters in FIGS. 5A, 5B, and 5C for the progressively larger inflationof patch 400 provides optimal apposition of the needle through thevessel wall regardless of diameter. Thus, a variable diameter system iscreated in which the same catheter may be employed in lumens throughoutthe body that are within a range of diameters. This is useful becausemost medical products are limited to very tight constraints (typicallywithin 0.5 mm) in which lumens they may be used. A system as describedin this invention may accommodate several millimeters of variability inthe luminal diameters for which they are useful.

The above catheter designs and variations thereon, are described inpublished U.S. Pat. Nos. 6,547,803; 6,860,867; 7,547,294; 7,666,163 and7,691,080, the full disclosures of which are incorporated herein byreference. Co-pending application Ser. No. 10/691,119, assigned to theassignee of the present application, describes the ability of substancesdelivered by direct injection into the adventitial and pericardialtissues of the heart to rapidly and evenly distribute within the hearttissues, even to locations remote from the site of injection. The fulldisclosure of that co-pending application is also incorporated herein byreference. An alternative needle catheter design suitable for deliveringthe therapeutic or diagnostic agents of the present invention will bedescribed below. That particular catheter design is described andclaimed in U.S. Pat. No. 7,141,041, the full disclosure of which isincorporated herein by reference.

Referring now to FIG. 6, a needle injection catheter 310 constructed inaccordance with the principles of the present invention comprises acatheter body 312 having a distal end 314 and a proximal 316. Usually, aguide wire lumen 313 will be provided in a distal nose 352 of thecatheter, although over-the-wire and embodiments which do not requireguide wire placement will also be within the scope of the presentinvention. A two-port hub 320 is attached to the proximal end 316 of thecatheter body 312 and includes a first port 322 for delivery of ahydraulic fluid, e.g., using a syringe 324, and a second port 326 fordelivering the neuromodulating agent, e.g., using a syringe 328. Areciprocatable, deflectable needle 330 is mounted near the distal end ofthe catheter body 312 and is shown in its laterally advancedconfiguration in FIG. 6.

Referring now to FIG. 7, the proximal end 314 of the catheter body 312has a main lumen 336 which holds the needle 330, a reciprocatable piston338, and a hydraulic fluid delivery tube 340. The piston 338 is mountedto slide over a rail 342 and is fixedly attached to the needle 330.Thus, by delivering a pressurized hydraulic fluid through a lumen 341tube 340 into a bellows structure 344, the piston 338 may be advancedaxially toward the distal tip in order to cause the needle to passthrough a deflection path 350 formed in a catheter nose 352.

As can be seen in FIG. 8, the catheter 310 may be positioned in a bloodvessel BV, over a guide wire GW in a conventional manner. Distaladvancement of the piston 338 causes the needle 330 to advance intotissue T surrounding the lumen adjacent to the catheter when it ispresent in the blood vessel. The therapeutic or diagnostic agents maythen be introduced through the port 326 using syringe 328 in order tointroduce a plume P of agent in the cardiac tissue, as illustrated inFIG. 8. The plume P will be within or adjacent to the region of tissuedamage as described above.

The needle 330 may extend the entire length of the catheter body 312 or,more usually, will extend only partially into the therapeutic ordiagnostic agents delivery lumen 337 in the tube 340. A proximal end ofthe needle can form a sliding seal with the lumen 337 to permitpressurized delivery of the agent through the needle.

The needle 330 will be composed of an elastic material, typically anelastic or super elastic metal, typically being nitinol or other superelastic metal. Alternatively, the needle 330 could be formed from anon-elastically deformable or malleable metal which is shaped as itpasses through a deflection path. The use of non-elastically deformablemetals, however, is less preferred since such metals will generally notretain their straightened configuration after they pass through thedeflection path.

The bellows structure 344 may be made by depositing by parylene oranother conformal polymer layer onto a mandrel and then dissolving themandrel from within the polymer shell structure. Alternatively, thebellows 344 could be made from an elastomeric material to form a balloonstructure. In a still further alternative, a spring structure can beutilized in, on, or over the bellows in order to drive the bellows to aclosed position in the absence of pressurized hydraulic fluid therein.

After the therapeutic material is delivered through the needle 330, asshown in FIG. 8, the needle is retracted and the catheter eitherrepositioned for further agent delivery or withdrawn. In someembodiments, the needle will be retracted simply by aspirating thehydraulic fluid from the bellows 344. In other embodiments, needleretraction may be assisted by a return spring, e.g., locked between adistal face of the piston 338 and a proximal wall of the distal tip 352(not shown) and/or by a pull wire attached to the piston and runningthrough lumen 341.

The perivascular space is the potential space over the outer surface ofa “vascular wall” of either an artery or vein. Referring to FIG. 9, atypical arterial wall is shown in cross-section where the endothelium Eis the layer of the wall which is exposed to the blood vessel lumen L.Underlying the endothelium is the basement membrane BM which in turn issurrounded by the intima I. The intima, in turn, is surrounded by theinternal elastic lamina IEL over which is located the media M. In turn,the media is covered by the external elastic lamina (EEL) which acts asthe outer barrier separating the arterial wall, shown collectively as W,from the adventitial layer A. Usually, the perivascular space will beconsidered anything lying beyond the external elastic lamina EEL,including regions within the adventitia and beyond.

Turning now to FIG. 10A-C, the renal arterial location and structure areshown. In FIG. 10A, the aorta (Ao) is shown as the central artery of thebody, with the right renal artery (RRA) and left renal artery (LRA)branching from the aorta to lead blood into the kidneys. For example,the right renal artery leads oxygenated blood into the right kidney(RK). In FIG. 10B, the nerves (N) that lead from the aorta to the kidneyare displayed. The nerves are shown to surround the renal artery,running roughly parallel but along a somewhat tortuous and branchingroute from the aorta to the kidney. The cross-section along line 10C-10Cof FIG. 10B is then shown in FIG. 10C. As seen in this cross-sectionalrepresentation of a renal artery, the nerves (N) that lead from aorta tokidney run through the arterial adventitia (A) and in close proximitybut outside the external elastic lamina (EEL). The entire arterial crosssection is shown in this FIG. 10C, with the lumen (L) surrounded by,from inside to outside, the endothelium (E), the intima (I), theinternal elastic lamina (IEL), the media (M), the external elasticlamina (EEL), and finally the adventitia (A).

As illustrated in FIG. 11A-F, the methods of the present invention maybe used to place an injection or infusion catheter similar to thoseillustrated by FIGS. 1-5 into a vessel as illustrated in FIG. 10C and toinject a plume (P) of neuromodulating agent into the adventitia (A) suchthat the agent comes in contact with the nerves (N) that innervate theadventitia of the renal artery. As can be seen in FIG. 11A, a catheterin the same state as FIG. 4A, wherein an actuator is shielding a needleso that the actuator can be navigated through the vessels of the bodywithout scraping the needle against the vessel walls and causing injury,is inserted into an artery that has a media (M), an adventitia (A), andnerves (N) within the adventitia and just outside the media. Across-section along line 11D-11D from FIG. 11A is shown in FIG. 11D. Itcan be seen from this cross section that a therapeutic instrumentcomprised similarly to those in FIGS. 1-3, with an actuator (12)attached to a catheter (20) and a needle (14) disposed within theactuator.

Turning to FIGS. 11B and 11E, we see the same system as that in FIGS.11A and 11D, again where FIG. 11E is a view of the cross-section alongline 11E-11E from FIG. 11B. In FIGS. 11B and 11E, however, the actuatorthat has been filled with a fluid, causing the actuator to unfurl andexpand, and the needle aperture to penetrate the media and into theadventitia where nerves are located. After the needle penetrates to theadventitia, a plume (P) that consists of either diagnostic agent such asradio-opaque contrast medium or neuromodulating agent such as botulinumtoxin or guanethidine or a combination of the diagnostic and therapeuticagents is delivered beyond the EEL and into the adventitia. The plume(P) begins to migrate circumferentially and longitudinally within theadventitia and begins to come into contact with the nerve fibers thatrun through the adventitia. At this point, the physician may begin tonotice the therapeutic effects. Usually, the plume P that is used todiagnose the presence of the injection and the location of the injectionis in the range from 10 to 100 μl, more often around 50 μl. The plumewill usually indicate one of four outcomes: (1) that the needle haspenetrated into the adventitia and the plume begins to diffuse in asmooth pattern around and along the outside of the vessel, (2) that theplume follows the track of a sidebranch artery, in which case the needleaperture has been located into the sidebranch rather than in theadventitia, (3) that the plume follows the track of the artery in whichthe catheter is located, indicating that the needle has not penetratedthe vessel wall and fluid is escaping back into the main vessel lumen,or (4) that a tightly constricted plume is forming and not diffusinglongitudinally or cyndrically around the vessel, indicating that theneedle aperture is located inward from the EEL and inside the media orintima. The plume is therefore useful to the operating physician todetermine the appropriateness of continued injection versus deflationand repositioning of the actuator at a new treatment site.

In FIGS. 11C and 11F, where FIG. 11F is a cross-sectional view acrossthe line 11F-11F from FIG. 11C, one can see that after the plume is usedto diagnose the appropriate tissue location of injection, furtherinjection can be performed to surround the vessel with theneuromodulating agent. The extent of the final plume P* is usually fullycircumferential around the artery and usually travels longitudinally byat least 1 cm when the injection volume is between 300 μl and 1 ml. Inmany cases, less than these volumes may be required in order to observea therapeutic benefit to the patient's hypertension. At this point, theneuromodulating agent has penetrated the nerves around the entireartery, blocking the transmission of nerve signals and thereby creatingchemical, neuromodulating, or biological denervation.

FIG. 12 illustrates the process by which botulinum toxin interrupts thetransmission of nerve signals. In FIG. 12, it is seen that the toxin,here labeled “botulinum neurotoxin”, is comprised of a “light chain” anda “heavy chain”. The heavy chain is critical to bind the botulinumneurotoxin receptors and allow the botulinum neurotoxin to enter thecell by endocytosis. Once in the cell, the light chain of botulinumneurotoxin separates from the heavy chain in this illustration andcleaves SNARE proteins “syntaxin”, “synaptobrefin”, and “SNAP 25”. Whenthese SNARE proteins are cleaved, vesicles containing acetylchoninecannot be released from the nerve into the synaptic cleft. While this isshown in FIG. 12 for the neuromuscular junction, this is merelyillustrative of the mechanism by which botulinum neurotoxin interactswith nerve cells, as it has also been shown that botulinum neurotoxinsprohibit the release of acetylcholine and noradrenaline from other nervejunctions.

The following Experiments are offered by way of illustration, not by wayof limitation.

EXPERIMENTAL

Studies were performed in a normal porcine model to determine ifadventitial delivery of guanethidine could reduce kidney norepinephrine(NE), a marker for successful denervation. Successful denervation iswell known to reduce blood pressure in hypertensive patients.

Renal denervation evidenced by NE reduction: Guanethidine monosulfatewas diluted in 0.9% NaCl to a concentration of 12.5 mg/ml, then furtherdiluted in iodinated contrast medium to a final concentration of 10mg/ml. This solution was injected using a Mercator MedSystems BullfrogMicro-Infusion Catheter (further described in this application anddetailed in FIG. 11A-F) into the adventitia of both renal arteries,approximately halfway between the aorta and the hilum of the kidney. Theinjection was monitored with X-ray visualization of contrast medium toconfirm adventitial distribution, which was confirmed to carry theinjectate longitudinally and circumferentially around the artery, aswell as transversely into the perivascular tissue. No injection was madeinto control animals, and historical controls from Connors 2004 wereused as comparators.

Twenty-eight days after injection, kidneys and renal arteries wereharvested. Kidney samples were taken using the method established byConnors 2004. Briefly, cortex tissue samples from the poles of thekidneys were removed and sectioned into approximately 100 mg segments.From each kidney, samples from each pole were pooled for analysis. Renalarteries were perfusion fixed in 10% neutral buffered formalin ansubmitted for histopathology.

Histology: Arteries appeared normal at 28 days, with no signs ofvascular toxicity. Perivascular indications of denervation were apparentfrom lymphocyte, macrophage and plasma cell infiltration intoadventitial nerve bodies, with nerve degeneration characterized byhypervacuolization and eosinophilia.

Radio-immunoassay: NE levels in renal cortex tissue revealed averagelevels of 64 nanograms (ng) NE per gram (g) of renal cortex. Whencompared to normal controls of 450 ng/g, this represents a reduction inrenal cortex NE of 86%. These data are shown in FIG. 13.

Additional comparison can be made to the reduction in renal cortex NEfrom surgical denervation, which Connors 2004 reported as 97% and Krum2008 reported as 94%. Furthermore, the reduction in kidney NE reportedwith the use of radiofrequency catheter ablation of the renal nerves hasbeen reported as 86%. The radiofrequency method has since been used inclinical trials and evidence has been shown that the ablation of thenerves, resulting in reduced NE by 86%, directly translates to reducedhypertension in patients, with reports of systolic pressure reduction of27 mmHg and diastolic reduction of 17 mmHg, twelve months aftertreatment.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

What is claimed is:
 1. A device for the treatment of hypertension comprising: an inflatable balloon that, when inflated, positions a needle within a vessel wall for the delivery of fluids outside and around the vessel wall; an electrically resistive heating element positioned along the pathway of the injected fluid, wherein the heating element is connected to a proximal energy source and control circuitry; and a thermosensor positioned distal to the resistive heating element, wherein the thermosensor is connected to a proximal energy source and is capable of feeding back a signal to the control circuitry for the purpose of controlling the temperature of the resistive heating element.
 2. The device of claim 1, wherein the heating element heats the fluids.
 3. The device of claim 1, wherein the thermosensor is configured to control a temperature of the fluids such that nerves within the vessel wall are heated from 42 C to 50 C.
 4. The device of claim 1, wherein the thermosensor is configured to heat the fluids to a temperature of at least from 42 C to 50 C.
 5. The device of claim 1, wherein the vessel is a blood vessel.
 6. The device of claim 5, wherein the inflatable balloon and needle are configured to position the needle into tissue bound on the inside by the external elastic lamina of said blood vessel and bound on the outside by the outer extent of the adventitial and perivascular connective tissues that surround the blood vessel.
 7. The device of claim 5, wherein the blood vessel is a vein or an artery.
 8. The device of claim 5, wherein the blood vessel is a renal vein or a renal artery.
 9. The device of claim 8, wherein the inflatable balloon and needle are configured to position the needle into tissue bound on the inside by the external elastic lamina of said renal artery or renal vein and bound on the outside by the outer extent of the adventitial and perivascular connective tissues that surround the renal artery or renal vein.
 10. The device of claim 2, comprising a fluid source that comprises the fluids to be heated by the heating element upon contact therewith, thereby making the fluid therapeutically effective in treating hypertension.
 11. The device of claim 10, wherein the fluids comprise a diagnostic agent.
 12. The device of claim 10, comprising a source of a diagnostic agent.
 13. The device of claim 12, wherein the diagnostic agent comprises a radio-opaque contrast medium.
 14. A system for treating hypertension, said system comprising: a catheter adapted to be introduced into a patient's vasculature; a needle adapted to be deployed from the catheter through a blood vessel wall into the adventitia surrounding the blood vessel; and a source of a neuromodulating agent which can be delivered through the needle into the adventitia to lower the systemic blood pressure of the patient by a therapeutically beneficial amount.
 15. The system of claim 14, wherein the needle is advanceable in a direction substantially normal to the blood vessel wall to a depth in the range from 300 μm to 3 mm.
 16. The system of claim 14, wherein the catheter is configured to deliver an amount of the neuromodulating agent that is effective to lower systemic blood pressure by a therapeutically beneficial amount.
 17. The system of claim 14, wherein the neuromodulating agent comprises a neurotoxin or neurotoxin fragment.
 18. The system of claim 17, wherein the neurotoxin is a botulinum neurotoxin or fragment thereof
 19. The system of claim 18, wherein system is configured to deliver an amount of the neurotoxin, wherein the neurotoxin comprises active botulinum neurotoxin, and wherein the amount is between 10 picograms and 25 nanograms of active botulinum neurotoxin, between 50 picograms and 10 nanograms of active botulinum neurotoxin, or between 100 picograms and 2.5 nanograms of active botulinum neurotoxin.
 20. The system of claim 14, wherein the source of neuromodulating agent is also a source of a diagnostic agent, wherein the neuromodulating agent is mixed with the diagnostic agent.
 21. The system of claim 14, comprising a source of a diagnostic agent.
 22. The system of claim 21, wherein the source of diagnostic agent is configured to allow delivery of the diagnostic agent into adventitial prior to the delivery of the neuromodulating agent.
 23. The system of claim 21, wherein the diagnostic agent comprises a radio-opaque contrast medium.
 24. The system of claim 14, wherein the blood vessel is an artery or a vein.
 25. The system of claim 24, wherein the artery is a renal artery, or the vein is a renal vein. 